Glucose-dependent insulinotropic polypeptide confers early phase insulin release to oral glucose in rats: Demonstration by a receptor antagonist

A novel GIP receptor antagonist was developed to evaluate the acute role of glucose-dependent insulinotropic polypeptide (GIP) in the insulin response to oral glucose in rats. Antisera to an extracellular epitope of the GIP r eceptor (GIPR) detected immunoreactive GIPR on rat pancreatic beta-cells. P urified GIPR antibody (GIPR Ab) specifically displaced GIP binding to the r eceptor and blocked GIP-mediated increases in intracellular cAMP. When deli vered to rats by ip injection, GIPR Ab had a half-life of approximately 4 d ays. Treatment with GIPR Ab (1 mu g/g BW) blocked the potentiation of gluco se-stimulated insulin secretion by GIP (60 pmol) but not glucagon-like pept ide-1 (GLP-1, 60 pmol) in anesthetized rats. The insulin response to oral g lucose was delayed in conscious unrestrained rats that were pretreated with GIPR Ab. Plasma insulin levels were similar to 35% lower at 10 min in GIPR Ab treated animals compared with controls. As a result, the glucose excurs ion was greater in the GIPR Ab treated group. Fasting plasma glucose levels were not altered by GIPR Ab. We conclude that release of GIP following ora l glucose may act as an anticipatory signal to pancreatic beta-cells to pro mote rapid release of insulin for glucose disposal.